Blood purification therapy for the treatment of renal insufficiency employs a module such as hemodialyzer, blood filter or hemodialysis filter which uses a dialyzer membrane or an ultrafiltration membrane made of cellulose, that is a natural material, cellulose diacetate or cellulose triacetate that is a derivative of the former, or a polymer such as polysulfone, polymethyl methacrylate or polyacrylonitrile as a separating member for removing uremic toxin and waste products from the blood. A module employing a hollow fiber membrane as the separating member is particularly useful in the field of dialyzer in view of such advantages as the reduction in the amount of blood extracorporeally circulated, high efficiency of removing substances from the blood and high productivity in producing the module.
Among the membrane materials described above, polysulfone resins are viewed as promising materials having high water permeability that is most fitted to the advancement in the dialysis technology. A semi-permeable membrane formed from polysulfone alone, however, has low affinity with blood since the polysulfone resin is hydrophobic, and cannot be used directly in blood treatment due to a trouble of air locking.
To solve the problem described above, it has been proposed to make a hydrophilic membrane from a polysulfone resin mixed with a hydrophilic polymer, including a method of mixing a polyhydric alcohol such as polyethylene glycol (see, for example, Japanese Unexamined Patent Publication (Kokai) No. 61-232860 and Japanese Unexamined Patent Publication (Kokai) No. 58-114702).
A method of adding polyvinyl pyrrolidone has also been disclosed (see, for example, Japanese Examined Patent Publication (Kokoku) No. 5-54373 and Japanese Examined Patent Publication (Kokoku) No. 6-75667).
The latter method that uses polyvinyl pyrrolidone is considered to be capable of solving the problems described above with such advantages as safety and economy. However, the method of rendering hydrophilicity to the membrane by adding polyvinyl pyrrolidone has such a problem that the polyvinyl pyrrolidone elutes into the purified blood during dialysis. When much of the polyvinyl pyrrolidone elutes during dialysis, polyvinyl pyrrolidone which is foreign to the human body accumulates within the body over a long period of dialysis treatment, thus giving rise to the possibility of side effects and complications. Accordingly, tolerable amount of polyvinyl pyrrolidone elution is specified in the Approval Standard for Dialysis-type Artificial Kidney Apparatus. The standard is based on the amount of polyvinyl pyrrolidone elution determined in terms of UV absorbance. Technologies for examining the effect of controlling the amount of elution according to the standard have been disclosed (see, for example, Japanese Patent No. 3314861, Japanese Unexamined Patent Publication (Kokai) No. 6-165926 and Japanese Unexamined Patent Publication (Kokai) No. 2000-350926).
The problems described above can be solved by the methods described above. However, in the method of rendering hydrophilicity to the membrane by adding polyvinyl pyrrolidone, performance of the permselective separation membrane depends heavily on the amount of polyvinyl pyrrolidone contained in the inner surface of the membrane that makes contact with the blood (hereinafter referred to as inner surface) and in the opposing outer surface of the membrane (hereinafter referred to as outer surface), and therefore it is important to optimize the content of polyvinyl pyrrolidone. For example, while compatibility of the membrane with the blood can be ensured by increasing the content of polyvinyl pyrrolidone in the inner surface, too much polyvinyl pyrrolidone contained in the surface causes more polyvinyl pyrrolidone to elute into the blood. This is undesirable since accumulation of the eluted polyvinyl pyrrolidone gives rise to the possibility of side effects and complications through long period of dialysis.
When too much polyvinyl pyrrolidone is contained in the outer surface, on the other hand, the possibility of endotoxin (endotoxin system), which is contained in the dialysis solution and has high hydrophilicity, infiltrating into the blood side increases, which may lead to side effects such as pyrexia. Another problem may also arise such as difficulty in assembling the module, since the hollow fiber membranes adhere to each other via polyvinyl pyrrolidone which exists on the outer surface when the membranes are dried.
It is preferable to decrease the amount of polyvinyl pyrrolidone existing in the outer surface, for the purpose of suppressing polyvinyl pyrrolidone from infiltrating into the blood side. However, this leads to lower hydrophilicity of the outer surface, and therefore to lower affinity with the physiological saline that is used for wetting when the hollow fiber membrane is returned to wet state after it has been dried for assembling the module. This may cause a problem of lower priming property which indicates the degree of air purging during the wetting operation.
In order to solve the problems described above, such a method has been proposed as setting the amount of polyvinyl pyrrolidone contained in the dense layer of the inner surface of the permselective separation membrane within a particular range, and setting the amount of polyvinyl pyrrolidone contained in the dense layer of the inner surface at least 1.1 times the amount of polyvinyl pyrrolidone contained in the outer surface of the permselective separation membrane (see, Japanese Unexamined Patent Publication (Kokai) No. 6-165926). In other words, this technology improves compatibility with blood by increasing the amount of polyvinyl pyrrolidone contained in the dense layer of the inner surface, and suppressing the hollow fiber membranes from sticking to each other when the membranes are dried, by decreasing the amount of polyvinyl pyrrolidone contained in the outer surface. This technology not only solves the problem of sticking of the membranes but also mitigates the problem of infiltration of the endotoxin (endotoxin system) contained in the dialysis solution into the blood side. However, since the amount of polyvinyl pyrrolidone contained in the outer surface is too small, it may lead to another problem of lower priming performance.
A method has been disclosed for mitigating one of the problems described above, that endotoxin (endotoxin system) contained in the dialysis solution infiltrates to the blood side, by setting the contents of polyvinyl pyrrolidone in the inner surface, the outer surface and the intermediate layer of the permselective separation membrane to particular values (see, for example, Japanese Unexamined Patent Publication (Kokai) No. 2001-38170). This method solves one of the problems described above. However, it does not solve the other problems, for example, that the priming performance lowers. Also since the permselective separation membrane made by this method has high aperture ratio of 25% or higher in the outer surface which results in lower strength of the membrane, it may cause problems such as leakage of blood.
Further, methods have been disclosed for improving the compatibility of the membrane with blood and mitigating the problem of elution of polyvinyl pyrrolidone into the blood, by setting the content of polyvinyl pyrrolidone in the inner surface of the permselective separation membrane to a particular value (see, for example, Japanese Unexamined Patent Publication (Kokai) No. 6-296686, Japanese Unexamined Patent Publication (Kokai) No. 11-309355 and Japanese Unexamined Patent Publication (Kokai) No. 2000-157852).
The documents cited above make no mention at all to the content of polyvinyl pyrrolidone in the outer surface of the hollow fiber membrane. As a consequence, these technologies cannot solve all of the problems related to the content of polyvinyl pyrrolidone in the outer surface.
Among the problems described above, the problem of endotoxin infiltrating into the blood side is addressed by a method which is based on such a property of endotoxin (endotoxin system) that the molecule thereof has a hydrophobic moiety and can be easily adsorbed onto a hydrophobic substance (see, for example, Japanese Unexamined Patent Publication (Kokai) No. 2000-254222). Specifically, this method involves setting the proportion of polyvinyl pyrrolidone to the hydrophobic polymer contained in the outer surface of the hollow fiber membrane within a range from 5 to 25%. This method is effective in suppressing the endotoxin from infiltrating into the blood side. However, achieving this effect requires it to clean the outer surface of the membrane so as to remove the polyvinyl pyrrolidone therefrom, which takes much time leading to economical disadvantage. In Example of the patent cited above, for example, one hour each is taken in showering of warm water of 60° C. and in cleaning with hot water of 110° C.
Decreasing the content of polyvinyl pyrrolidone in the outer surface is also effective in suppressing the endotoxin from infiltrating into the blood side. However, this decreases the hydrophilicity of the outer surface, and results in lower affinity with the physiological saline used for wetting when the hollow fiber membrane is returned to wet state after it has been dried for assembling the module. This may cause a problem of lower priming property which indicates the degree of air purging during the wetting operation. In order to solve this problem, it has been disclosed to add a hydrophilic compound such as glycerin (see, for example, Japanese Unexamined Patent Publication (Kokai) No. 2001-190934 and Japanese Patent No. 3193262). However, this method has a problem that the hydrophilic compound acts as a foreign matter during dialysis and that the hydrophilic compound is susceptible to degradation such as photo-deterioration, thus having an adverse effect on the stability of the module in storage. There is also such a problem that it becomes difficult to bond with an adhesive when securing the hollow fiber membrane to the module during assembly of the module.
Meanwhile a membrane having particular values of aperture ratio and pore area in the outer surface of the membrane has been disclosed (see, for example, Japanese Unexamined Patent Publication (Kokai) No. 2000-140589).
The content of polyvinyl pyrrolidone in the inner surface has a significant influence also on the selectivity of solute separation by the permselective separation membrane. When treating the blood of a patient of chronic renal insufficiency, it is necessary to minimize the leakage of albumin which is a useful protein, while removing other proteins of low molecular weights. With regard to the selectivity of the separation membrane, a polysulfone-based permselective separation membrane having albumin permeability of 0.5 to 0.0001% has been disclosed (see, Japanese Unexamined Patent Publication (Kokai) No. 11-309356). It is true that the method disclosed in this patent document has an advantage of decreasing the albumin permeability to a very low level. However, the permselective separation membrane obtained with this method has a problem of low removal ratio of α1-microglobulin. In recent years much attention has been attracted to the dialysis complications as the number of patients who rely on long-term dialysis treatment increases. Accordingly, range of substances to be removed by dialysis has been expanding from substances of low molecular weights such as urea, uric acid and creatinine to those of medium molecular weights of around 5,000 Daltons and further to low-molecular weight proteins of 10,000 Daltons or larger. Thus while it is required to efficiently remove uremia-causing substances having molecular weights represented by (α1-microglobulin contained in blood, the method of Japanese Unexamined Patent Publication (Kokai) No. 11-309356 which provides low selectivity of separating proteins cannot meet this requirement.
Meanwhile a polysulfone-based permselective separation membrane has been disclosed which has sieving coefficient of egg-white albumin of 0.2 or higher (see, Japanese Unexamined Patent Publication (Kokai) No. 7-289863). The permselective separation membrane disclosed in the document has an advantage of being capable of efficiently removing uremia-causing substances. However, it has a disadvantage of having a high removal ratio for useful proteins. Thus there is strong demand for the development of a permselective separation membrane that has well-balanced capabilities of removing both albumin and α1-microglobulin.
For a case where a hollow fiber membrane bundle is dried by the irradiation of microwave, such a method is proposed to lower the output power of microwave when the mean water content is from 20 to 70% by weight (see, Japanese Unexamined Patent Publication (Kokai) No. 2003-175320, Japanese Unexamined Patent Publication (Kokai) No. 2003-175321 and Japanese Unexamined Patent Publication (Kokai) No. 2003-175322). While these documents describe a sequence of drying first with output power of 30 kW, then about 21 kW, no mention is made to a technique of irradiating with microwave under a reduced pressure. Although the normal drying process and the use of microwave are described, it is not described to combine microwave and reduced pressure. While the documents show consideration to the uniformity of drying between the central region and the periphery of the hollow fiber membrane bundle, no consideration is given to the uniformity of drying in the longitudinal direction of the hollow fiber membrane bundle.